Flashmelt oral dosage formulation

ABSTRACT

There is provided granules for the production of flash-melt pharmaceutical oral dosage forms. In addition to one or more medicaments, the granules are composed of an excipient combination consisting of a superdisintegrant, a dispersing agent, a distributing agent, and a binder and may also include other conventional ingredients such as sweetening and flavoring agents. The subject granules are advantageous in that they are stable and can be prepared without the aid of solvents and without the need for special environments or handling. Dosage forms, especially tablets, prepared therefrom on conventional equipment disintegrate in the mouth in under about twenty five seconds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/056,410 filed Mar. 27, 2008, now abandoned, which is a continuationof U.S. application Ser. No. 10/979,556 filed Nov. 2, 2004, nowabandoned, which is a continuation of U.S. application Ser. No.10/920,851 filed Aug. 18, 2004, now pending, which is a continuation ofU.S. application Ser. No. 09/973,226 filed Oct. 9, 2001, which is acontinuation-in-part of U.S. application Ser. No. 09/589,340 filed Jun.7, 2000, now abandoned, which is a continuation in-part of U.S.application Ser. No. 09/547,948 filed Apr. 12, 2000, now abandoned.

FIELD OF THE INVENTION

The present invention relates to a formulation for solid pharmaceuticaloral dosage forms that rapidly disperses in the mouth.

BACKGROUND OF THE INVENTION

There are a variety of solid pharmaceutical dosage forms that rapidlydissolve or disintegrate in a glass of water or in the gastrointestinaltract. Such dosage forms have been known in the art for many years. Theobvious advantages of the convenience of carrying dosage forms that willdissolve or effervesce in water to release medicaments are well known.The therapeutic need of having an oral dosage form that will rapidlydissolve or disintegrate in the mouth for situations where immediatemedication is necessary and water is not available has long beenrecognized.

Initially, a distinction must be drawn between flash-melt dosage formsand rapidly disintegrating dosage forms. The former are intended todissolve or disintegrate in the mouth of the patient in less than oneminute whereas the latter are intended for primary dissolution ordisintegration within 3 to 20 minutes in the acidic medium of thestomach or a container of water. The recognized test for rapidlydisintegrating dosage forms is disintegration time in 0.1 N hydrochloricacid. Those of ordinary skill in the art will appreciate that therequirements for formulating dosage forms to meet these criteria mustnecessarily be different since the conditions, particularly pH, in themouth and the stomach are quite different. More importantly, the time inwhich a dosage form must dissolve or disintegrate in the mouth isnecessarily much shorter than in the stomach with the obvious exceptionof dosage forms, e.g. lozenges, that are specifically formulated toslowly dissolve in the mouth.

Another consideration common to most if not all dosage form formulationsintended for flash-melt or rapid disintegration is the need to takeprecautions in the preparation, packaging, handling and storing of thefinished dosage forms since they tend to be both hygroscopic andfriable. Dosage forms dependent on effervescence to promote theirdisintegration are particularly susceptible to moisture and must bepackaged with special wrapping, stoppers, packets of drying agent andthe like.

Regardless of such potential problems, there is still an acute need fordosage forms that can rapidly dissolve or disintegrate for the obviousbenefits of having a therapeutic dosage of the medicament containedtherein available for absorption in a very short time. In addition tothe benefits of rapid availability, flash-melt dosage forms areadvantageous for administration of medicaments to patients such as thevery young, the elderly, the non-compliant and those with a physicalimpairment that makes it difficult if not impossible to swallow anintact dosage form. Flash-melt dosage forms are further a conveniencefor situations where potable water may not be readily available ordesirable. Medicaments amenable to such dosage forms would includesedatives, hypnotics, antipsychotics, motion sickness medication, mildstimulants such as caffeine and the like.

Those of ordinary skill in the art are aware that there are two basiccompounding concepts recognized for the preparation of rapidlydissolving/disintegrating dosage forms. The first of these, particularlysuited for the preparation of flash-melt dosage forms, is freeze dryingwherein a cake or wafer is prepared from a freeze-dried solution orsuspension of medicament and suitable excipients in water or othersolvents. Such wafers dissolve very rapidly on the tongue, i.e. withinabout ten seconds, due to a combination of a high affinity for moistureresulting from the freeze drying process and a very high porosity, whichpromotes rapid ingress of saliva. While such dosage forms are capable ofrapid disintegration/dissolution in the mouth, the freeze drying processsuffers from several disadvantages, primary among which is the fact thata solution or a stable suspension of the medicament must be formedbefore it can be freeze dried. While not always the case, typically suchsolutions are aqueous and, therefore, not suited to formulatingmedicaments sensitive to water. The process itself is typicallylaborious and time-consuming. Finally, the resultant dosage forms, inaddition to being hygroscopic, tend to be very soft and, therefore,require special moisture- and impact-resistant packaging and requirecareful handling prior to administration.

The second major technology utilized in the manufacture of rapidlydisintegrating dosage forms is based on special grades of sugars such asmannitol, sorbitol and the like in combination with superdisintegrants.The latter are excipients that are characterized by a special wickingcapacity to channel water into the interior of the dosage form, or byrapid swelling in water, both of which act to hasten disintegration. Itis also known to enhance dissolution of dosage forms by the inclusion ofeffervescent combinations, typically sodium bicarbonate and a weak acid,such as citric acid. As noted above, effervescent formulations requirespecial moisture resistant packaging as even very small levels ofmoisture may be sufficient to initiate the effervescent reaction.Techniques, such as fluidized bed granulation, are recognized as beinguseful in the preparation of such formulations. Too often, however, suchtechnologies require a specific, very costly plant including specialhandling equipment, controlled-humidity environments and the like. Inspite of such measures, dosage forms produced by such techniquestypically require moisture resistant packaging, the need to include inthe packaging packets or capsules of moisture absorbing agents and thelike.

An example of a teaching of the incorporation of super disintegrants indosage form formulations to enhance dissolution is WO 98/030640, FMCCorporation. It is disclosed therein that, for cost considerations, upto 90% of a group of super disintegrants including cross-linkedcellulose, cross-linked carboxymethyl cellulose, cross-linked starch,croscarmellose alkali metal salt, crospovidone, alkali metal starchglycolate and the like can be replaced by a co-disintegrant. Includedamong the latter group are natural diatomaceous silica, a synthetichydrous alkaline earth metal calcium silicate and a porous hydrophiliczeolite. The weight ratio of super disintegrant to co-disintegrant isstated as from 4:1 to 1:10, preferably 2-1:1. There is no indication ofany recognition of benefits to be derived from the formulation otherthan the obvious consideration of cost savings since theco-disintegrants are less expensive and the combination is stated toaccomplish the desired results.

In contrast, Japanese patent 10114655, Kyowa Hakko Kogyo KK discloses aformulation intended for rapid dissolution in the stomach that cancontain up to 30% by weight of a superdisintegrant, such as crospovidoneor hydroxypropylcellulose, croscarmellose and the like and up to 30% ofa neutral or basic ingredient including magnesium aluminum metasilicate,calcium silicate, a phosphoric acid salt or a metal hydroxide. Thedosage form is intended for medicaments that produce a gel at acidic pH.

There are numerous other examples of specific formulations that utilizeone or more of the techniques or mechanisms discussed above. For themost part, however, they also possess one or more of the enumerateddisadvantages to some degree, e.g. it is difficult or expensive toproduce dosage forms by such techniques, the resulting dosage forms arefriable or are sensitive to environmental factors such as moisture.There continues to be the need for a formulation that mitigates oreliminates these disadvantages, yet yields a flash-melt dosage form thatwill disintegrate in the mouth within about 25 seconds. Suchformulations are provided in accordance with the present invention.

SUMMARY OF THE INVENTION

According to a first embodiment of the present invention is provided aflash-melt pharmaceutical dosage form comprising a medicament, asuperdisintegrant, a dispersing agent and a binder wherein saidmedicament is aripiprazole, entecavir, cefprozil, pravastatin,captopril, gatifloxacin, desquinolone, omapatrilat or irbesartan andwherein said dispersing agent is calcium silicate, magnesium trisilicateor silicic acid.

According to a first series of embodiments of the present invention areprovided flash-melt pharmaceutical dosage forms as described hereinwherein greater than 50% of said dispersing agent by weight is comprisedof calcium silicate.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein whereingreater than 80% of said dispersing agent by weight is comprised ofcalcium silicate.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saiddispersing agent is calcium silicate.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saiddispersing agent comprises from about 20 to about 70 percent by weightof said dispersing agent based on the total weight of said dosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saiddispersing agent comprises from about 35 to about 45 percent by weightof said dispersing agent based on the total weight of said dosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is crystalline.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is amorphous.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is ortho-, meta- or alpha triclinic-calcium silicate.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is alpha triclinic-calcium silicate.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is comprised of a combination of alphatriclinic-calcium silicate and at least one other pharmaceutical gradeof calcium silicate wherein said alpha triclinic-calcium silicatecomprises from about 10% to about 90% by weight of said combination.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate has a surface area of 1.0 m²/gm to 210 m²/gm, bulkdensity of 0.075 g/cc to 0.90 g/cc, true density of 1.70 g/cc to 2.90g/cc and volatile content of less than 1% to 14% w/w.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is alpha triclinic calcium silicate that has a surfacearea of about 1.3 m²/gm, bulk density of about 0.63 g/cc, true densityof about 2.90 g/cc and volatile content of less than 1% w/w.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is ortho crystalline calcium silicate that has asurface area of about 0.98 m²/gm, bulk density of about 0.492 g/cc, truedensity of about 3.252 g/cc and volatile content of less than 1% w/w.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is meta crystalline calcium silicate that has a surfacearea of about 2.5 m²/gm, bulk density of about 0.867 g/cc, true densityof about 2.940 g/cc and volatile content of less than 1% w/w.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is crystalline calcium silicate that has a surface areaof about 90.4 m²/gm, bulk density of about 0.094 g/cc, true density ofabout 2.596 g/cc and volatile content of less than 1% w/w.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is amorphous calcium silicate that has a surface areaof about 191.3 m²/gm, bulk density of about 0.120 g/cc, true density ofabout 2.314 g/cc and volatile content of about less than 14% w/w.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is amorphous calcium silicate that has a surface areaof about 103.0 m²/gm, bulk density of about 0.130 g/cc, true density ofabout 1.702 g/cc and volatile content of about less than 14% w/w.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidcalcium silicate is amorphous calcium silicate that has a surface areaof about 209 m²/gm, bulk density of about 0.075 g/cc, true density ofabout 2.035 g/cc and volatile content of about less than 14% w/w.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidmedicament comprises not more than about 30 percent by weight of saidmedicament based on the total weight of said dosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidmedicament comprises not more than about 15 percent by weight of saidmedicament based on the total weight of said dosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidmedicament is selected from the group consisting of aripiprazole,entecavir, cefprozil, pravastatin, captopril, gatifloxacin,desquinolone, omapatrilat and irbesartan.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidmedicament is aripiprazole.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent comprises from about 3 to about 15 percent byweight of said superdisintegrant agent based on the total weight of saiddosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent comprises from about 4 to about 10 percent byweight of said superdisintegrant agent based on the total weight of saiddosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent comprises from about 4 to about 8 percent byweight of said superdisintegrant agent based on the total weight of saiddosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent comprises from about 5 to about 7 percent byweight of said superdisintegrant agent based on the total weight of saiddosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent comprises from about 8 to about 12 percent byweight of said superdisintegrant agent based on the total weight of saiddosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent comprises from about 9 to about 10 percent byweight of said superdisintegrant agent based on the total weight of saiddosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent is crospovidone, croscarmellose sodium, sodiumstarch glycolate, low-substituted hydroxypropyl cellulose orpregelatinized starch.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent is crospovidone or croscarmellose sodium.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidsuperdisintegrant agent is crospovidone and croscarmellose sodium.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein, whereinbased on the total weight of said dosage form, said crospovidonecomprises from about 6 to about 8 percent by weight of said crospovidoneand said croscarmellose sodium comprises from about 2 to about 4 percentby weight of said croscarmellose sodium.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saiddistributing agent comprises from about 1 to about 10 percent by weightof said distributing agent based on the total weight of said dosageform.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saiddistributing agent comprises from about 1.5 to about 3 percent by weightof said distributing agent based on the total weight of said dosageform.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saiddistributing agent is amorphous silica, fumed silica, diatomaceousearth, talc, kaolin or magnesium aluminum trisilicate.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saiddistributing agent comprises from about 10 to about 50 percent by weightof said binder based on the total weight of said dosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saiddistributing agent comprises from about 12 to about 20 percent by weightof said binder based on the total weight of said dosage form.

According to other embodiments of the present invention are providedflash-melt pharmaceutical dosage forms as described herein wherein saidbinder is microcrystalline cellulose, hydroxypropyl cellulose, ethylcellulose, lactose, mannitol or calcium phosphate.

Yet other embodiments or aspects of the present invention reside in thecombination of one or more of the embodiments or aspects describedherein.

Yet other embodiments or aspects of the present invention are describedbelow.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the terms “a medicament”, “a superdisintegrant”, “adispersing agent”, “a distributing agent” or “a binder” means that oneor more of agents belonging to each class may be suitably employed inthe present invention unless otherwise specified. Furthermore, if agentsbelonging to a particular class are referred to in the alternative, itis understood that one or more of said agents may be suitably employed.Thus for example, two or more superdisintegrants may be employed unlessotherwise specified. The flash-melt pharmaceutical dosage forms thepresent invention may be prepared by dry granulation of the excipientswith the medicament and suitable conventional ingredients, such asflavoring and sweetening agents, without the use of any solvent, to formstable granules that can be readily compressed into dosage forms onconventional equipment without the need for special handling techniques.

The active medicament may comprise up to about 30% by weight,particularly up to about 15% by weight, of the formulation, depending onthe amount required for a therapeutically effective dosage and factorssuch as its capacity to be directly granulated, the amount offlavoring/sweetening agents required to mask the taste or bitternessthereof and the like. It is within the scope of the present invention toutilize medicaments that are coated for taste or other reason in thesubject formulations provided that the coatings do not interfere witheither the compounding or the disintegration of the tablets.

Suitable superdisintegrants include crospovidone, croscarmellose sodium,sodium starch glycolate, low-substituted hydroxypropylcellulose,pregelatinized starch and the like. Crospovidone can be utilized inlarge amounts without causing a formulation containing it to have apropensity to gel.

Suitable dispersing agents, also sometimes referred to in the art asanticaking agents, include calcium silicate-ortho, meta and alphatriclinic forms thereof, magnesium trisilicate-ortho and meta formsthereof and silicic acid. Calcium silicate is the preferred dispersingagent. Particularly preferred is a crystalline alpha triclinic calciumsilicate, commercially available from Aldrich Chemical Company whichmeets the following specifications: 1.3 m²/gm surface area; 0.63 g/ccbulk density; 2.90 g/cc true density; and <1% w/w volatiles. Alsoparticularly preferred is a crystalline alpha triclinic calciumsilicate, commercially available from J.M. Huber Inc., TomitaPharmaceutical Co., Aldrich Chemical Company which meets the followingspecifications: 1.0 to 15 m²/gm surface area; 0.50 to 0.63 g/cc bulkdensity; 2.40 to 2.90 g/cc true density; and <1% w/w volatiles. Avariety of pharmaceutical grades of calcium silicate available fromother vendors, as shown in Table 1, have also been found to producesatisfactory flash-melt dosage forms as well. These include ortho andmeta forms of calcium silicate available from Alfa-Aesar, syntheticcalcium silicates Micro-cel C and Micro-cel E, available from CeliteCorp, Hubersorb 600 NF and Hubersorb 250 NF available from J. M. HuberCorp, and combinations of various grades thereof. These products havebeen found to cover the following range of specifications for calciumsilicate: 1.0 m²/gm to 210 m²/gm surface area; 0.075 g/cc to 0.90 g/ccbulk density; 1.70 g/cc to 2.90 g/cc true density; and <1% to 14% w/wvolatiles. Table 1 lists the individual specifications for each of thematerials obtained from the vendors listed above.

TABLE 1 Surface True Volatiles area Bulk Density Density (% SourceDescription m²/gm g/cc (±s.d.) g/cc w/w) Aldrich CaSiO3 < 1.3 0.627(0.020) 2.934 0.50 200 mesh (crystalline, alpha triclinic) Alfa2CaO•SiO2 0.98 0.492 (0.003) 3.252 0.02 Aesar (crystalline, ortho) AlfaCaSiO3 2.5 0.867 (0.009) 2.940 0.50 Aesar (crystalline, meta) CelciteMicro-cel E 90.4 0.094 (0.006) 2.596 0.94 (crystalline) CelciteMicro-cel C 191.3 0.120 (0.006) 2.314 5.11 (amorphous) JM Hubersorb103.0 0.130 (0.008) 1.702 9.90 Huber 250NF (amorphous) JM Hubersorb 209 0.075 2.035 13.8 Huber 600NF (<0.001) (amorphous)

Alpha triclinic calcium silicate is advantageously combined in thesubject formulations with at least one other pharmaceutical grade ofcalcium silicate wherein the alpha triclinic form would comprise fromabout 10% to about 90% by weight of the combination. In contrast to itsuse in conventional tabletting formulations, it is considered unexpectedthat the dispersing agent, i.e. calcium silicate, is the primaryconstituent of the excipient combination of the subject formulationssince it is generally recognized by those of ordinary skill in the artas being poorly compressible.

Examples of suitable distributing agents for the excipient combinationof the subject formulations include amorphous silica, fumed silica,diatomaceous earth, talc, kaolin, magnesium aluminum trisilicate and thelike.

Suitable binders are those that also function as a wicking ordistributing agent in that they act to promote water intake into dosageforms made therefrom. Suitable binders include carbohydrates such as,microcrystalline cellulose, hydroxypropyl cellulose, ethyl cellulose,starch, lactose, and also, mannitol and calcium phosphate.Microcrystalline cellulose is commercially available as Avicel® PH(pharmaceutical grade) from FMC Corporation, Philadelphia, Pa.,particularly Avicel® PH 101, PH 102, PH 103, PH 112, PH 200, PH 301, PH302 and Ceolus. Microcrystalline cellulose is also available fromMendell, Penwest Company, Patterson, N.Y., as Emcocel® 90M and Emcocel®50M, which could be used satisfactorily.

The formulations of the present invention may contain other conventionalingredients found in similar preparations known in the art andrecognized as approved for use in preparations to be taken into thebody. These would include, for example, natural and artificial flavors,polyols such as mannitol, sorbitol, maltitol and xylitol, artificialsweetening agents such as, N-α-L-Aspartyl-L-phenylalanine 1-methyl ester(aspartame) and6-methyl-3,4-dihydro-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide,particularly the potassium salt thereof (acesulfame K), flavor adjunctssuch as tartaric acid, tabletting lubricants, such as magnesiumstearate, and the like. Those skilled in the art of pharmaceuticalcompounding will appreciate that the amount of flavoring and sweeteningagents, if any, present in the formulations of the present inventionwill be directly proportional to the taste or bitterness of themedicament. The flavoring and sweetening agents do not serve to coat themedicament, but are adequate to mask the objectionable taste of themedicaments in homogeneous admixture therewith. In general, the total ofsuch conventional ingredients will not exceed about 32 percent,preferably from about 25 to about 30 percent by weight based on thetotal weight of the formulation.

The medicament in the formulations of the present invention typicallywill not exceed about 30 percent by weight, preferably from about 1 toabout 15 percent by weight of the formulation. Those of ordinary skillin the art will appreciate that the physical characteristics of themedicament itself, i.e. its particle size and morphology, will directlyinfluence its limiting content in the subject formulations. Clearly,there has to be sufficient medicament in the dosage form produced formthe subject formulations to provide a therapeutically effective dosage.While solid dosage forms can be prepared from the formulations of thepresent invention by any recognized technique, including wetgranulation, it is a particular advantage that the formulations can bedry granulated without the use of specialized equipment and conditions,thereby making them suitable for the formulation of medicaments that aresensitive to moisture and high temperatures.

Examples of medicaments that can be formulated into flash-melt tabletsin accordance with the present invention include, without intendedlimitation, antihistamines, anti-motion sickness agents, analgesics,anti-inflammatory agents, antibiotics, cholesterol lowering agents,anti-anxiety agents, anti-hypertensives, anti-cancer agents, hypnotics,anti-ulcer agents, coronary dilators, antivirals, anti-psychotics,anti-depressants, neuromuscular agents, anti-diarrheals, hypoglycemicagents, thyroid suppressors, anabolic agents, antisposmodics,antimigraine agents, diuretics, stimulants, decongestants, uterinerelaxants, anti-arrhythmics, male erectile dysfunction compounds, Maxi-Kchannel openers or neuroprotective agents for the treatment of stroke orAlzheimer's disease and therapeutically appropriate combinationsthereof. Specific therapeutic agents falling into the foregoingcategories include, again without intended limitation, aripiprazole,ibuprofen, aspirin, acetaminophen, chlorpheniramine maleate,psuedoephedrine, diphenhydramine HCl, ranitidine, phenylpropanolamine,cimetidine, loperamide, meclizine, caffeine, entecavir, cefprozil,melatonergic agonists, pravastatin, captopril, fosinopril, irbesartan,omapatrilat, gatifloxacin and desquinolone and therapeuticallyappropriate combinations thereof.

As stated above, a decided advantage of the formulation of the presentinvention is that it can be dry-granulated into stable, fine granulesthat can be directly compressed into pharmaceutically elegant flash-meltoral dosage forms, e.g. tablets, caplets, wafers and the like.Preferably, the granules for flash-melt dosage forms in accordance withthe present invention are formed in two steps. The process comprisesinitially forming granules, referred to herein as the intragranulation,by blending all of the medicament, the dispersing agent, (distributingagent), other conventional ingredients as described above and a portionof each of the superdisintegrant, binder and tabletting lubricanttogether in a suitable mixer to assure uniform distribution throughout.A conventional V-blender is a preferred apparatus for this step. While aminor portion of the dispersing agent may be omitted from theintragranulation, it is preferred that all be incorporated therein. Theblended mixture is then compacted in a conventional roller compactorhaving an orifice such that the compacts thereof are in the form ofribbons. Alternately, a slugging process can be used. The compacts fromthe roller compactor or the slugs from the slugger are passed through afine screen, e.g. a 30 mesh (600 microns) screen, thereby breaking theminto granules between about 150 and 400 microns in size. Theintragranulation granules thus-prepared are thereafter blended in asuitable mixer with the remaining ingredients, i.e., superdisintegrant,binder and lubricant, referred to herein as the extragranulationingredients, to form a final blend that can be directly compressed intopharmaceutical dosage forms utilizing conventional equipment such as atablet press. Rather than directly compress the final blend uponformation, since it is stable, it can be stored and subsequently pressedinto dosage forms at a later time. It is a decided advantage ofparticular aspects of the subject invention that these operations arecarried out without the need to resort to special handling such astaking precautions against any moisture coming in contact with theingredients or the granules, and without the use of specially controlledtemperature and humidity conditions.

The intragranulation comprises from about 80 to 99, preferably fromabout 85 to 95, most preferably about 90, percent by weight of the finalblend. Based on the weight of the final blend, the intragranulationpreferably comprises up to about 30 percent by weight, preferably fromabout 6 to 20 percent by weight, of the binder, up to about 5 percent byweight, preferably from about 2 to 4 percent by weight, of thesuperdisintegrant, and all of the dispersing agent and the distributingagent. The binder and superdisintegrant are divided between theintragranulation and the extragranulation ingredients in weight ratiosof approximately 2:1 to 4:1 for the binder and 0.5:2.0 to 2.0:0.5 forthe superdisintegrant. The conventional tabletting lubricant is dividedapproximately equally between the intragranulation and theextragranulation ingredients.

The final blend is formed by mixing the intragranulation and theextragranulation components of the excipient combination, adding theremaining tabletting lubricant thereto and blending until uniform.Alternatively, a direct compression approach can be utilized in whichall of the ingredients with the exception of the tabletting lubricantare mixed in a suitable blender, such as a conventional V-blender, bygeometrically building the entire mass of the formulation via sequentialblending for three minutes after each addition, and finally adding thelubricant to the mixture after all other ingredients have been blended.

Tablets compressed on a conventional tablet press from the final blendobtained from either a one-step granulation or a direct compressionblend, were pharmaceutically elegant and disintegrated in water withinten seconds. A tablet is considered as disintegrated when it has totallybroken down to granules and there are no discernible lumps remaining.Since the medicament is not intimately bound to any of the ingredientsof the formulation, it is released within the same time period. Anotheradvantage of particular aspects of the subject formulations is thatdosage forms can be manufactured therefrom which are robust and, hence,avoid the need for specialized unit dose packaging and careful handlingduring manufacture or use as is often the case with present dosageforms. The dosage forms prepared from formulations of particular aspectsof the present invention can be packaged in conventional blister packsor in HDPE bottles.

It is understood that various other embodiments and modifications in thepractice of the invention will be apparent to, and can be readily madeby, those of ordinary skill in the art without departing form the scopeand spirit of the invention as described above. Accordingly, it is notintended that the scope of the claims appended hereto be limited to theexact description set forth above, but rather that the claims beconstrued as encompassing all of the features of patentable novelty thatreside in the present invention, including all the features andembodiments that would be treated as equivalents thereof by thoseskilled in the art to which the invention pertains. The invention isfurther described with reference to the following experimental work.

Means of manufacturing aripiprazole drug substance for formulatingaccording to the present flashmelt invention may be performed asfollows.

Aripiprazole Hydrate

The aripiprazole hydrate (grains) of the present invention have thephysicochemical properties given in (1)-(5) below. This aripiprazolehydrate is described hereinafter as “Aripiprazole Hydrate A”.

(1) It has an endothermic curve which is substantially the same as thethermogravimetric/differential thermal analysis (heating rate 5° C./min)endothermic curve shown in FIG. 1. Specifically, it is characterized bythe appearance of a small peak at about 71° C. and a gradual endothermicpeak around 60° C. to 120° C.

(2) It has an ¹H-NMR spectrum which is substantially the same as the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 2. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(3) It has a powder x-ray diffraction spectrum which is substantiallythe same as the powder x-ray diffraction spectrum shown in FIG. 3.Specifically, it has characteristic peaks at 2θ=12.6°, 15.4°, 17.3°,18.0°, 18.6°, 22.5° and 24.8°.

(4) It has clear infrared absorption bands at 2951, 2822, 1692, 1577,1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

(5) It has a mean grain size of 50 μm or less.

Method of Manufacturing Aripiprazole Hydrate A

Aripiprazole Hydrate A is manufactured by milling conventionalaripiprazole hydrate.

Conventional milling methods can be used to mill the aripiprazolehydrate. For example, the aripiprazole hydrate can be milled in amilling machine. A widely used milling machine can be used, such as anatomizer, pin mill, jet mill or ball mill. Of these, the atomizer ispreferred.

Regarding the specific milling conditions when using an atomizer, arotational speed of 5000-15000 rpm could be used for the main axis, forexample, with a feed rotation of 10-30 rpm and a screen hole size of 1-5mm.

The mean grain size of the Aripiprazole Hydrate A obtained by millingshould normally be 50 μm or less, preferably 30 μm or less. Mean grainsize can be ascertained by the grain size measurement method describedhereinafter.

Grain Size Measurement: 0.1 g of the grains to be measured weresuspended in a 20 ml n-hexane solution of 0.5 g soy lecithin, and grainsize was measured using a size distribution meter (Microtrack HRA,Microtrack Co.).

Aripiprazole Anhydride Crystals

The aripiprazole anhydride crystals of the present invention have thephysicochemical properties given in (6)-(10) below. These aripiprazoleanhydride crystals are referred to hereinafter as “AripiprazoleAnhydride Crystals B”.

(6) They have an ¹H-NMR spectrum which is substantially the same as the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 4. Specifically, they havecharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(7) They have a powder x-ray diffraction spectrum which is substantiallythe same as the powder x-ray diffraction spectrum shown in FIG. 5.Specifically, they have characteristic peaks at 2θ=11.0°, 16.6°, 19.3°,20.3° and 22.1°.

(8) They have clear infrared absorption bands at 2945, 2812, 1678, 1627,1448, 1377, 1173, 960 and 779 cm⁻¹ on the IR (KBr) spectrum.

(9) They exhibit an endothermic peak near about 141.5° C. inthermogravimetric/differential thermal analysis (heating rate 5°C./min).

(10) They exhibit an endothermic peak near about 140.7° C. indifferential scanning calorimetry (heating rate 5° C./min).

Aripiprazole Anhydride Crystals B of the present invention have lowhygroscopicity. For example, Aripiprazole Anhydride Crystals B of thepresent invention maintain a water content of 0.4% or less after 24hours inside a dessicator set at a temperature of 60° C. and a humidityof 100%.

Well-known methods of measuring water content can be used as long asthey are methods commonly used for measuring the water content ofcrystals. For example, a method such as the Karl Fischer method can beused.

Method of Manufacturing Aripiprazole Anhydride Crystals B

The Aripiprazole Anhydride Crystals B of the present invention areprepared for example by heating the aforementioned Aripiprazole HydrateA at 90-125° C. The heating time is generally about 3-50 hours, butcannot be stated unconditionally since it differs depending on heatingtemperature. The heating time and heating temperature are inverselyrelated, so that for example the heating time will be longer the lowerthe heating temperature, and shorter the higher the heating temperature.Specifically, if the heating temperature of Aripiprazole Hydrate A is100° C., the heating time should normally be 18 hours or more orpreferably about 24 hours. If the heating temperature of AripiprazoleHydrate A is 120° C., on the other hand, the heating time can be about 3hours. The Aripiprazole Anhydride Crystals B of the present inventioncan be prepared with certainty by heating Aripiprazole Hydrate A forabout 18 hours at 100° C., and then heating it for about 3 hours at 120°C. The Aripiprazole Anhydride Crystals B of the present invention canalso be obtained if the heating time is extended still further, but thisis not economical.

Furthermore, the Aripiprazole Anhydride Crystals B of the presentinvention are prepared for example by heating conventional aripiprazoleanhydride crystals at 90-125° C. The heating time is generally about3-50 hours, but cannot be stated unconditionally since it differsdepending on heating temperature. The heating time and heatingtemperature are inversely related, so that for example the heating timewill be longer the lower the heating temperature, and shorter the higherthe heating temperature. Specifically, if the heating temperature of thearipiprazole anhydride crystals is 100° C., the heating time can beabout 4 hours, and if the heating temperature is 120° C. the heatingtime can be about 3 hours.

The aripiprazole anhydride crystals which are the raw material forpreparing the Aripiprazole Anhydride Crystals B of the present inventionare prepared for example by Method a or b below.

Method a:

Aripiprazole anhydride crystals are prepared by well-known methods, asby reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with1-(2,3-dichlorophenyl)piperadine and recrystallizing the resulting rawaripiprazole crystals with ethanol as described in Example 1 of JapaneseUnexamined Patent Publication No. 191256/1990.

Method b:

Aripirazole anhydride crystals are prepared by heating conventionalaripiprazole hydrate at a temperature of at least 60° C. and less than90° C. The heating time is generally about 1-30 hours, but cannot bestated unconditionally since it differs depending on heatingtemperature. The heating time and heating temperature are inverselyrelated, so that for example the heating time will be longer the lowerthe heating temperature, and shorter the higher the heating temperature.Specifically, if the heating temperature of the aripiprazole hydrate isabout 60° C., the heating time can be about 8 hours, while if theheating temperature is 80° C., the heating time can be about 4 hours.

The Method b is described in the Proceedings of the 4th Japanese-KoreanSymposium on Separation Technology (Oct. 6-8, 1996).

Furthermore, the Aripiprazole Anhydride Crystals B of the presentinvention are prepared for example by heating conventional aripiprazolehydrate at 90-125° C. The heating time is generally about 3-50 hours,but cannot be stated unconditionally since it differs depending onheating temperature. The heating time and heating temperature areinversely related, so that for example the heating time will be longerthe lower the heating temperature, and shorter the higher the heatingtemperature. Specifically, if the heating temperature of thearipiprazole hydrate is 100° C., the heating time can be about 24 hours,while if the heating temperature is 120° C., the heating time can beabout 3 hours.

The aripiprazole hydrate which is the raw material for preparing theAripiprazole Anhydride Crystals B of the present invention is preparedfor example by Method c below.

Method c:

Aripiprazole hydrate is easily obtained by dissolving the aripiprazoleanhydride crystals obtained by Method a above in a hydrous solvent, andheating and then cooling the resulting solution. Using this method,aripiprazole hydrate is precipitated as crystals in the hydrous solvent.

An organic solvent containing water is usually used as the hydroussolvent. The organic solvent should be one which is miscible with water,such as for example an alcohol such as methanol, ethanol, propanol orisopropanol, a ketone such as acetone, an ether such as tetrahydrofuran,dimethylformamide, or a mixture thereof, with ethanol being particularlydesirable. The amount of water in the hydrous solvent can be 10-25% byweight of the solvent, or preferably close to 20% by weight.

As mentioned above, the Aripiprazole Anhydride Crystals B of the presentinvention are prepared by heating at 90-125° C. of said AripiprazoleHydrate A, conventional aripiprazole anhydride crystals or conventionalaripiprazole hydrate, and said Aripiprazole Hydrate A, conventionalaripiprazole anhydride crystals or conventional aripiprazole hydrate maybe used either individually or in combination.

The following examples used aripiprazole drug substance made by firstmilling the conventional hydrate of aripiprazole and then heating it toform the anhydrous form (anhydride B).

Example 1

Flash-melt tablets were prepared as follows:

Intragranulation:

Ingredient Percent w/w Mg. per tablet Xylitol (300) Xylisorb 26 52Avicel ® PH 102 12 24 Calcium Silicate 43.35 86.7 Crospovidone 3 6Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaricacid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 92.75185.5

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was then added and the mixtureblended for an additional three minutes. The blended formulation wascompacted at a pressure of 30-35 kgF/cm² in a commercial compactorequipped with an orifice such that the compacts therefrom are in theform of ribbons. The ribbons were passed through a 30 mesh (600 microns)screen to form stable granules of about 150 to 400 microns.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 92.75 185.5Avicel ® PH 200 3 6 Crospovidone 4 8 Magnesium stearate 0.25 0.5 Totalweight 100 200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.3 kP (3.5 SCU) and disintegrated in10 seconds in 5 ml of water. The final blend formulation demonstratedexcellent flow and was free of other problems such as chipping, cappingand sticking. It has been found that utilizing Avicel® PH 102 for theintragranulation and Avicel® PH 200 for the extragranulation ingredientenhanced the quality of the resultant tablets.

Example 2

Flash-melt tablets containing a combination of two grades of calciumsilicate were prepared as follows:

Intragranulation:

Ingredient Percent w/w Mg. per tablet Xylitol (300) Xylisorb 26 52Avicel ® PH 102 12 24 Calcium Silicate (crystalline, alpha 33.35 66.7triclinic) Hubersorb 600 NF (amorphous 10 20 calcium silicate)Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5Total weight 92.75 185.5

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofExample 1.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 92.75 185.5Avicel ® PH 200 3 6 Crospovidone 4 8 Magnesium stearate 0.25 0.5 Totalweight 100 200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.0 kP (3.1 SCU) and disintegrated in10 seconds in 5 ml of water.

Example 3

Flash-melt tablets containing aripiprazole, an antischizophrenic drug,were prepared as follows:

Intragranulation

Ingredient Percent w/w Mg. per tablet Aripiprazole 15 30 Xylitol (300)Xylisorb 25 50 Avicel ® PH 102 6 12 Calcium Silicate 37 74 Crospovidone3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Totalweight 94.4 188.8

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofExample 1.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 94.4 188.8Avicel ® PH 200 1.1 2.2 Crospovidone 4 8 Magnesium stearate 0.5 1 Totalweight 100 200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.0 kP (3.1 SCU) and disintegrated in10 seconds in 5 ml of water.

Example 4

Flash-melt tablets containing aripiprazole were prepared as follows:

Intragranulation:

Ingredient Percent w/w Mg. per tablet Aripiprazole 0.5 1 Xylitol (300)Xylisorb 27 54 Avicel ® PH 102 12 24 Calcium Silicate 42 84 Crospovidone3 6 Amorphous silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3Tartaric acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Totalweight 92.9 185.8

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofExample 1.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 92.9 185.8Avicel ® PH 200 2.6 5.2 Crospovidone 4 8 Magnesium stearate 0.5 1 Totalweight 100 200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.3 kP (3.5 SCU) and disintegrated in10 seconds in 5 ml of water.

Example 5

Flash-melt tablets can be prepared containing the antiviral medicamententecavir as follows:

Intragranulation:

Ingredient Percent w/w Mg. per tablet Entecavir 1 2 Xylitol (300)Xylisorb 26 52 Avicel ® PH 102 10 20 Calcium Silicate 45 90 Crospovidone4 8 Amorphous silica 2. 4 Aspartame 2 4 Wild cherry flavor 0.25 0.5Tartaric acid 2 4 Acesulfame K 2. 4 Magnesium stearate 0.25 0.5 Totalweight 94.5 189

The ingredients except for the magnesium stearate were blended in acommercial V-blender in geometric proportions for 5 minutes each untilall were added. The magnesium stearate was added and the mixture blendedfor an additional three minutes. The blended formulation was compacted,and screened to form stable granules in accordance with the procedure ofExample 1.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 94.5 189 Avicel ®PH 200 2 4 Crospovidone 3 6 Magnesium stearate 0.5 1 Total weight 100200

The intragranulation was placed in the blender and the Avicel® PH 200and crospovidone added thereto and blended for five minutes. Themagnesium stearate was then added and the mixture blended for anadditional three minutes to form the final blend. Tablets compressedtherefrom had a breaking force of 2.3 kP (3.5 SCU) and disintegrated in10 seconds in 5 ml of water. The percent w/w/ratios taught in thisexample can also be used to formulate a suitable formulation of thepresent invention comprising 0.1 mg of entecavir per unit dose.

Example 6

Flash-melt tablets can be prepared containing the antibiotic medicamentcefprozil as follows:

Intragranulation:

Ingredient Percent w/w Mg. per tablet Cefzil 25 125 Xylitol (300)Xylisorb 17 85 Avicel ® PH 102 6 30 Calcium Silicate 35 175 Crospovidone3 15 Amorphous silica 2. 10 Aspartame 2 10 Wild cherry flavor 0.25 1.25Tartaric acid 2 10 Acesulfame K 2 10 Magnesium stearate 0.25 1.25 Totalweight 94.5 472.5

Blend the ingredients except for the magnesium stearate in a commercialV-blender in geometric proportions for 5 minutes each until all areadded. Then add the magnesium stearate to the mixture prepared and mixfor an additional three minutes. Then compact the blended formulation,and screen to form stable granules in accordance with the procedure ofExample 1.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 94.5 472.5Avicel ® PH 200 2 10 Crospovidone 3 15 Magnesium stearate 0.5 2.5 Totalweight 100 500

Place the intragranulation in the blender and add the Avicel® PH 200 andcrospovidone thereto and blend for five minutes. Then add magnesiumstearate to the mixture and blend for an additional three minutes toform the final blend. Compress tablets therefrom to have a breakingforce of 2.5 kP (3.8 SCU) and a disintegration time of 10 seconds orless in 5 ml of water.

Example 7

Flash-melt tablets can be prepared containing the antihypertensivemedicament irbesartan as follows:

Intragranulation:

Ingredient Percent w/w Mg. per tablet Irbesartan 25 125 Xylitol (300)Xylisorb 17 85 Avicel ® PH 102 6. 30 Calcium Silicate 35 175Crospovidone 3 15 Amorphous silica 2 10 Aspartame 2 10 Wild cherryflavor 0.25 1.25 Tartaric acid 2 10 Acesulfame K 2 10 Magnesium stearate0.25 1.25 Total weight 94.5 472.5

Blend the ingredients except for the magnesium stearate in a commercialV-blender in geometric proportions for 5 minutes each until all areadded. Then add the magnesium stearate to the mixture prepared and mixfor an additional three minutes. Then compact the blended formulation,and screen to form stable granules in accordance with the procedure ofExample 1.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 94.5 472.5Avicel ® PH 20 2 10 Crospovidone 3 15 Magnesium stearate 0.5 2.5 Totalweight 100 500

Place the intragranulation in the blender and add the Avicel® PH 200 andcrospovidone thereto and blend for five minutes. Then add magnesiumstearate to the mixture and blend for an additional three minutes toform the final blend. Compress tablets therefrom to have a breakingforce of 2.5 kP (3.8 SCU) and a disintegration time of 10 seconds orless in 5 ml of water.

Example 8

Flash-melt tablets can be prepared containing the quinolone antibiotic,des-Quinolone as follows:

Intragranulation:

Ingredient Percent w/w Mg. per tablet des-Quinolone 20.0 100 Xylitol(300) Xylisorb 22.0 110 Avicel ® PH 102 6.0 30 Calcium Silicate 35.0 175Crospovidone 3.0 15 Amorphous silica 2.0 10 Aspartame 2.0 10 Wild cherryflavor 0.25 1.25 Tartaric acid Acesulfame K Magnesium starate 0.25 Totalweight

Blend the ingredients except for the magnesium stearate in a commercialV-blender in geometric proportions for 5 minutes each until all areadded. Then add the magnesium stearate to the mixture prepared and mixfor an additional three minutes. Then compact the blended formulation,and screen to form stable granules in accordance with the procedure ofExample 1.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 94.5 472.5Avicel ® PH 200 2.0 10.0 Crospovidone 3.0 15.0 Magnesium stearate 0.52.5 Total weight 100 500

Place the intragranulation in the blender and add the Avicel® PH 200 andcrospovidone thereto and blend for five minutes. Then add magnesiumstearate to the mixture and blend for an additional three minutes toform the final blend. Compress tablets therefrom to have a breakingforce of 2.5 kP (3.8 SCU) and a disintegration time of 10 seconds orless in 5 ml of water.

Example 9

Flash-melt tablets can be prepared containing the antibioticgatifloxacin (Tequin®), as a taste masked co-precipitate (30% w/wactive) to deliver 50 mg dose:

Intragranulation:

Ingredient Percent w/w Mg. per tablet Gatifloxacin:stearic acid 33.3166.7 co-precipitate Xylitol (300) Xylisorb 11.7 58.5 Avicel ® PH 1026.0 30 Calcium Silicate 32.0 160 Crospovidone 3.0 15 Amorphous silica2.0 10 Aspartame 2.0 10 Wild cherry flavor 0.25 1.23 Tartaric acid 2.010 Acesulfame K 2.0 10 Magnesium stearate 0.25 1.25 Total weight 94.5472.5

Blend the ingredients except for the magnesium stearate in a commercialV-blender in geometric proportions for 5 minutes each until all areadded. Then add the magnesium stearate to the mixture prepared and mixfor an additional three minutes. Then compact the blended formulation,and screen to form stable granules in accordance with the procedure ofExample 1.

Extragranulation Ingredients:

Ingredient Percent w/w Mg. per tablet Intragranulation 94.5 472.5Avicel ® PH 200 2.0 10.0 Crospovidone 3.0 15.0 Magnesium stearate 0.52.5 Total weight 100 500

Place the intragranulation in the blender and add the Avicel® PH 200 andcrospovidone thereto and blend for five minutes. Then add magnesiumstearate to the mixture and blend for an additional three minutes toform the final blend. Compress tablets therefrom to have a breakingforce of 2.5 kP (3.8 SCU) and a disintegration time of 10 seconds orless in 5 ml of water.

Example 10 Preparation of 2.5% w/w Aripiprazole Granulation for and 2 mgand 5 mg Tablets—Prototype II Intragranular Formulation:

Ingredient % w/w Aripiprazole 2.50 Xylitol, NF (Xylisorb 300) 21.15Microcrystalline Cellulose, NF (Avicel PH 102) 12.0 Calcium Silicate, NF42.0 Crospovidone, NF (XL-10) 3.0 Silicon Dioxide, NF (previouslyreferred to as 2.0 Amorphous Silica) Croscarmellose Sodium, NF 3.0Aspartame, NF 2.0 Flavor Creme de Vanilla 0.5 Tartaric Acid, NF 2Acesulfame K (E.P) 2.0 Magnesium stearate NF 0.25 Total 92.40

Intragranular Blend Preparation:

-   1. V-blender is chosen (that operates at 50 rpm speed) for the    mixing operation. In the first mixing step, aripiprazole is placed    in between Xylitol and Avicel PH 102 mixed in the V-blender for 10    minutes.-   2. In step 2, all other excipients are weighed out and placed in the    V-blender from step 1. Deaggregation was performed where necessary.    Mixing was done for 5 minutes.-   3. Finally, 0.25% magnesium stearate was added and blended for 3    minutes.-   4. For roller compaction Alexanderwerk WP 120X40 (roller compactor)    or other similar equipment can be used with the following    parameters:    -   Screw speed: 25 rpm Rolls speed: 5 rpm; Vacuum pressure: −105        mbar    -   Granulator: 75 rpm (fixed with top 4 mm screen and bottom 0.8 mm        or 20# screen)    -   Hydraulic pressure: 50 bar

Post Dry Granulation Blend Preparation:

Ingredient % w/w Granulation from step 4 92.40 Crospovidone, NF (XL-10)4.00 Microcrystalline Cellulose, NF 3.10 (Avicel ® PH 200) Magnesiumstearate, NF 0.5 Total 100.00

-   1. Based on the yield from step 4 calculate the new batch size and    place the intragranulation in the blender with the calculated    amounts of Avicel® PH 200 and crospovidone and blend for 5 minutes.-   2. Finally add the remaining amount of magnesium stearate and mix    for 3 minutes.    2 mg tablets may have a green pigment blend incorporated in the    extragranular portion above in a concentration of 0.3% w/w adjusted    by replacing the same amount of Avicel PH 200, i.e. the amount of    Avicel PH 200 will be 2.8% w/w.    5 mg tablets may have a blue aluminum lake incorporated in the    extragranular portion above in a concentration of 0.3% w/w adjusted    by replacing the same amount of Avicel PH 200, i.e. the amount of    Avicel PH 200 will be 2.8% w/w.

Tablet Compression:

-   1. Using the granulation prepared above, 2 mg potency aripiprazole    tablets can be prepared by compressing 80 mg weight tablets on any    conventional tablet press that can produce tablets having a breaking    force of 3.0 kP or 4.5 SCU.-   2. Using the granulation prepared above, 5 mg potency aripiprazole    tablets can be prepared by compressing 200 mg weight tablets on any    conventional tablet press that can produce tablets having a breaking    force of 3.0 kP or 4.5 SCU.

Example 11 Preparation of 10% w/w Aripiprazole Granulation for and 10mg, 15 mg, 20 mg and 30 mg Tablets—Prototype II IntragranularFormulation:

% Ingredient w/w Aripiprazole 10.00 Xylitol, NF (Xylisorb 300) 21.15Microcrystalline Cellulose, NF (Avicel PH 102) 10.0 Calcium Silicate, NF36.5 Crospovidone, NF (XL-10) 3.0 Silicon Dioxide, NF (previouslyreferred to as Amorphous Silica) 3.0 Croscarmellose Sodium, NF 2.0Aspartame, NF 2.0 Flavor Creme de Vanilla 0.5 Tartaric Acid, NF 2Acesulfame K (E.P) 2.0 Magnesium stearate NF 0.25 Total 92.40

Intragranular Blend Preparation:

-   1. V-blender is chosen (that operates at 50 rpm speed) for the    mixing operation. In the first mixing step, aripiprazole is placed    in between Xylitol and Avicel PH 102 mixed in the V-blender for 10    minutes.-   2. In step 2, all other excipients are weighed out and placed in the    V-blender from step 1. Deaggregation was performed where necessary.    Mixing was done for 5 minutes.-   3. Finally, 0.25% magnesium stearate was added and blended for 3    minutes.-   4. For roller compaction Alexanderwerk WP 120X40 (roller compactor)    or other similar equipment can be used with the following    parameters:    -   Screw speed: 25 rpm Rolls speed: 5 rpm; Vacuum pressure: −105        mbar    -   Granulator: 75 rpm (fixed with top 4 mm screen and bottom 0.8 mm        or 20# screen)    -   Hydraulic pressure: 50 bar

Post Dry Granulation Blend Preparation:

Ingredient % w/w Granulation from step 4 92.40 Crospovidone, NF (XL-10)4.00 Microcrystalline Cellulose, 3.10 NF (Avicel ® PH 200) Magnesiumstearate, NF 0.5 Total 100.00

-   5. Based on the yield from step 4 calculate the new batch size and    place the intragranulation in the blender with the calculated    amounts of Avicel® PH 200 and crospovidone and blend for 5 minutes.-   6. Finally add the remaining amount of magnesium stearate and mix    for 3 minutes.    -   10 mg tablets may have red iron oxide incorporated in the        extragranular portion above in a concentration of 0.04% w/w        adjusted by replacing the same amount of Avicel PH 200, i.e. the        amount of Avicel PH 200 will be 3.06% w/w.    -   15 mg tablets may have yellow iron oxide incorporated in the        extragranular portion above in a concentration of 0.3% w/w        adjusted by replacing the same amount of Avicel PH 200, i.e. the        amount of Avicel PH 200 will be 2.8% w/w.    -   20 mg tablets may be white in color and directly made from the        formulation shown above.    -   30 mg tablets may have red iron oxide incorporated in the        extragranular portion above in a concentration of 0.04% w/w        adjusted by replacing the same amount of Avicel PH 200, i.e. the        amount of Avicel PH 200 will be 3.06% w/w.

Tablet Compression:

-   1. Using the granulation prepared above, 10 mg potency aripiprazole    tablets can be prepared by compressing 100 mg weight tablets on any    conventional tablet press that can produce tablets having a breaking    force of 3.0 kP or 4.5 SCU.-   2. Using the granulation prepared above, 15 mg potency aripiprazole    tablets can be prepared by compressing 150 mg weight tablets on any    conventional tablet press that can produce tablets having a breaking    force of 3.0 kP or 4.5 SCU.-   3. Using the granulation prepared above, 20 mg potency aripiprazole    tablets can be prepared by compressing 200 mg weight tablets on any    conventional tablet press that can produce tablets having a breaking    force of 3.0 kP or 4.5 SCU.-   4. Using the granulation prepared above, 30 mg potency aripiprazole    tablets can be prepared by compressing 300 mg weight tablets on any    conventional tablet press that can produce tablets having a breaking    force of 3.0 kP or 4.5 SCU.

Pharmacokinetic Evaluation of 5 mg Flash-Melt Tablets—Prototypes I andII in Healthy Human Subjects

Open label, randomized, 2-period, 3 treatment control balanced crossoverstudy involving 33 healthy volunteers was conducted. Each subjectreceived one single 5 mg aripiprazole commercial tablet and a 5 mg doseof aripiprazole as either flash-melt Prototype I or flash-melt PrototypeII (both from a 2.5% w/w granulation).

COMPOSITION (mg/tablet) Prototype I Prototype II INGREDIENT 5 mg^(a) % 5mg^(b) % Aripiprazole 5.0 2.50 5.0 2.50 Calcium Silicate, NF 84.0 42.0084.0 42.00 Crospovidone NF (XL-10) 14.0 7.00 14.0 7.00 CroscarmelloseSodium, NF — — 6.0 3.00 Silicon Dioxide, NF (Syloid) 4.0 2.00 4.0 2.00Xylitol NF (Xylisorb ® 300) 48.3 24.15 42.3 21.15 MicrocrystallineCellulose NF 24 12.00 24 12.00 (Avicel ® PH 102) MicrocrystallineCellulose NF 6.2 3.10 6.2 3.10 (Avicel ® PH 200) Aspartame NF 4.0 2.004.0 2.00 Acesulfame Potassium 4.0 2.00 4.0 2.00 Creme de Vanilla(Natural & 1.0 0.50 1.0 0.50 Artifical Flavors) Tartaric Acid NF 4.02.00 4.0 2.00 Magnesium Stearate NF 1.5 0.75 1.5 0.75 Total 200 mg100.00 200 mg 100.0 ^(a)Product Identification Number: 337039-A005-050;^(b)Product Identification Number: 337039-A005-051

The disintegration time for both prototypes in the mouth was less than30 seconds. However, the two prototypes show different dissolution ratesin in-vitro dissolution tests using USP dissolution testing methods.Hence, the goal of this study was to evaluate if these differences wouldaffect in-vivo performance of the two prototypes.

The pharmacokinetic parameters from the clinical study are shown below:

AUC (INF) Dose Cmax Tmax* [ng · h/ F** Formulation (mg) N (ng/mL) (h)mL] (%) Commercial 5 33 21.4 3 1393 — Tablet (5.85) (1, 8)  (504)Flashmelt 5 16 17.8 4 1260 99.7 Prototype I (3.85)  (2, 12)  (474)(21.8) Flashmelt 5 17 21.0 4 1567 105 Prototype II (4.40) (1.5, 8)   (677) (18.4)Based on statistical analysis for C_(max) and AUC for the two prototypes(shown below) it was concluded that Prototype II is bioequivalent to theregular commercial aripiprazole tablets.

Point Parameter Ratio N Estimate 90% CI C_(max) B/A 16 0.8809 (0.7534,1.0300) C/A 17 0.9741 (0.8767, 1.0823) AUC (INF) B/A 16 0.9744 (0.9107,1.0491) C/A 17 1.0141 (0.9688, 1.0616) AUC (0-T) B/A 16 0.9647 (0.8941,1.0408) C/A 17 0.9979 (0.9438, 1.0551) A = Aripiprazole 5 mg commercialtablet B = Aripiprazole 5 mg flash-melt prototype I C = Aripiprazole 5mg flash-melt prototype II

One Year Chemical Stability of 2 mg and 30 mg Potency AripiprazoleFlash-Melt Tablets:

Shown below are the stability results for the 2 mg and 30 mg potencytablets placed on official IND stability testing. As seen from theresults, only one degradant is seen that shows growth under acceleratedconditions as well as at room temperature. This degradant has beenidentified as the N-oxide of aripiprazole (SFO-14094). The levels seenin the 2 mg tablets are significantly higher than those in the 30 mgtablets. Also, the N-oxide levels in the Prototype II formulation aresignificantly lower than those in the Prototype I formulation.

TABLE 1 Aripiprazole Flash-Melt Tablets; IND Stability Study -- 2-mgPrototype I (%) calculated from the area under the chromatagram peaknormalized for the area under the entire chromatogram Metabolite ofaripiprazole/ oxidation N-oxide of Unknown product aripiprazolearipiprazole Impurities Potency % % % % Total Potency Potency (ReportedTime Point and Storage RRT RRT RRT RRT Impurities (Result #1) (Result#2) Result) Condition 0.91 1.00 1.08 in ( ) % mg/tab mg/tab mg/tabInitial 0.06 99.94 — — 0.06 2.01 1.97 1.99  1 day @ 25 C./75% RH (open)0.07 99.86 0.07 — 0.14 1.98 NP 1.98  4 days @ 25 C./HIL/UVA (exposed0.06 99.81 0.13 — 0.19 1.97 NP 1.97  4 days @ 25 C./HIL/UVA (wrapped —99.95 0.05 — 0.05 2.02 NP 2.02  1 week @ 25 C./75% RH (open) 0.09 99.730.18 — 0.27 1.96 NP 1.96  2 wks @ 25 C./HIL/UVA (exposed) 0.08 99.710.15  .06 0.29 2.02 NP 2.02 (0.87)  2 wks @ 25 C./HIL/UVA (wrapped) 0.0599.90 0.05 — 0.10 1.98 NP 1.98  2 wks @ 25 C./60% RH (closed) 0.05 99.95— — 0.05 2.03 NP 2.03  2 wks @ 25 C./75% RH (open) 0.11 99.63 0.26 —0.37 1.98 NP 1.98  4 wks @ 25 C./60% RH (closed) 0.05 99.95 — — 0.052.01 NP 2.01  4 wks @ 40 C./75% RH (closed) 0.05 99.82 0.13 — 0.18 2.01NP 2.01  4 wks @ 50 C. (closed) 0.06 99.62 0.32 — 0.38 1.97 NP 1.97 13wks @ 25 C./60% RH (closed) 0.06 99.85 0.09 — 0.15 1.97 NP 1.97 13 wks @40 C./75% RH (closed) 0.09 99.46 0.45 — 0.54 1.95 NP 1.95 13 wks @ 50 C.(closed) 0.13 98.70 0.92 0.19 1.30 1.95 NP 1.95 (0.38) 26 wks @ 25C./60% RH (closed) 0.05 99.81 0.14 — 0.19 2.05 NP 2.05 26 wks @ 40C./75% RH (closed) 0.11 99.18 0.71 — 0.82 2.03 NP 2.03 52 wks @ −15 C.(closed) — 100.00 — — 0.00 2.05 NP 2.05 52 wks @ 25 C./60% RH (closed) —99.77 0.23 — 0.23 1.97 NP 1.97 RRT = relative retention time (relativeto the active compound, aripiprazole) during the chromatography analysisComments: “—” indicates that no peak was detected or that the peakmeasured less than the reporting limit (<0.05 I.I.) “NP” indicates, “NotPerformed”

TABLE 2 Aripiprazole Flash-Melt Tablets; IND Stability Study -- 2-mgPrototype II (%) calculated from the area under the chromatogram peaknormalized for the area under the entire chromatogram Metabolite ofaripiprazole/ oxidation N-oxide of Unknown product aripiprazolearipiprazole Impurities Potency % % % % Total Potency Potency (ReportedTime Point and Storage RRT RRT RRT RRT Impurities (Result #1) (Result#2) Result) Condition 0.91 1.00 1.08 in ( ) % mg/tab mg/tab mg/tabInitial 0.05 99.95 — — 0.05 2.05 2.04 2.05  1 day @ 25 C./75% RH (open)0.07 99.86 0.07 — 0.14 2.01 NP 2.01  4 days @ 25 C./HIL/UVA (exposed0.06 99.86 0.08 — 0.14 2.00 NP 2.00  4 days @ 25 C./HIL/UVA (wrapped0.06 99.89 0.06 — 0.11 2.00 NP 2.00  1 week @ 25 C./75% RH (open) 0.0899.80 0.12 — 0.20 2.00 NP 2.00  2 wks @ 25 C./HIL/UVA (exposed) 0.0999.74 0.12 0.06 0.26 2.00 NP 2.00 (0.87)  2 wks @ 25 C./HIL/UVA(wrapped) 0.05 99.95 — — 0.05 2.02 NP 2.02  2 wks @ 25 C./60% RH(closed) 0.06 99.89 0.05 — 0.11 2.00 NP 2.00  2 wks @ 25 C./75% RH(open) 0.10 99.72 0.18 — 0.28 1.99 NP 1.99  4 wks @ 25 C./60% RH(closed) 0.05 99.95 — — 0.05 2.01 NP 2.01  4 wks @ 40 C./75% RH (closed)0.05 99.90 0.05 — 0.10 2.04 NP 2.04  4 wks @ 50 C. (closed) 0.07 99.680.25 — 0.32 2.02 NP 2.02 13 wks @ 25 C./60% RH (closed) 0.06 99.88 0.06— 0.12 2.00 NP 2.00 13 wks @ 40 C./75% RH (closed) 0.08 99.63 0.29 —0.37 1.98 NP 1.98 13 wks @ 50 C. (closed) 0.12 98.89 0.74 0.20 1.11 1.98NP 1.98 (0.38) 26 wks @ 25 C./60% RH (closed) 0.06 99.86 0.08 — 0.142.06 NP 2.06 26 wks @ 40 C./75% RH (closed) 0.16 99.29 0.55 — 0.71 2.02NP 2.02 52 wks @ −15 C. (closed) — 100.00 — — 0.00 2.01 NP 2.01 52 wks @25 C./60% RH (closed) — 99.89 0.11 — 0.11 2.02 NP 2.02 RRT = relativeretention time (relative to the active compound, aripiprazole) duringthe chromatography analysis Comments: “—” indicates that no peak wasdetected or that the peak measured less than the reporting limit (<0.05I.I.) “NP” indicates, “Not Performed”

TABLE 3 Aripiprazole Flash-Melt Tablets; IND Stability Study -- 30-mgPrototype I (%) calculated from the area under the chromatogram peaknormalized for the area under the entire chromatogram Metabolite ofaripiprazole/ oxidation N-oxide of Unknown product aripiprazolearipiprazole Impurities Potency % % % % Total Potency Potency (ReportedTime Point and Storage RRT RRT RRT RRT Impurities (Result #1) (Result#2) Result) Condition 0.91 1.00 1.08 in ( ) % mg/tab mg/tab mg/tabInitial 0.06 99.94 — — 0.06 29.54 29.90 29.7  1 day @ 25 C./75% RH(open) 0.07 99.88 0.05 — 0.12 28.98 NP 29.0  4 days @ 25 C./HIL/UVA(exposed 0.05 99.89 0.06 — 0.11 29.39 NP 29.4  4 days @ 25 C./HIL/UVA(wrapped 0.06 99.89 0.05 — 0.11 29.41 NP 29.4  1 week @ 25 C./75% RH(open) 0.10 99.82 0.08 — 0.18 28.24 29.30 29.3*  2 wks @ 25 C./HIL/UVA(exposed) 0.05 99.85 0.10 — 0.15 29.52 NP 29.5  2 wks @ 25 C./HIL/UVA(wrapped) 0.05 99.89 0.06 — 0.11 29.98 NP 30.0  2 wks @ 25 C./60% RH(closed) 0.06 99.87 0.07 — 0.13 29.77 NP 29.8  2 wks @ 25 C./75% RH(open) 0.08 99.81 0.11 — 0.19 29.74 NP 29.7  4 wks @ 25 C./60% RH(closed) 0.05 99.95 — — 0.05 29.08 NP 29.1  4 wks @ 40 C./75% RH(closed) — 99.95 0.05 — 0.05 29.37 NP 29.4  4 wks @ 50 C. (closed) 0.0699.87 0.07 — 0.13 29.70 NP 29.7 13 wks @ 25 C./60% RH (closed) 0.0699.90 0.05 — 0.10 29.73 NP 29.7 13 wks @ 40 C./75% RH (closed) 0.0699.85 0.09 — 0.15 29.89 NP 29.9 13 wks @ 50 C. (closed) 0.06 99.77 0.17— 0.23 29.74 NP 29.7 26 wks @ 25 C./60% RH (closed) 0.05 99.91 0.04 —0.09 29.26 NP 29.3 26 wks @ 40 C./75% RH (closed) 0.06 99.81 0.13 — 0.1929.41 NP 29.4 52 wks @ −15 C. (closed) 0.05 99.95 — — 0.05 29.70 NP 29.752 wks @ 25 C./60% RH (closed) 0.06 99.88 0.06 — 0.12 29.90 NP 29.9 RRT= relative retention time (relative to the active compound,aripiprazole) during the chromatography analysis Comments: “—” indicatesthat no peak was detected or that the peak measured less than thereporting limit (<0.05 I.I.) “NP” indicates, “Not Performed” *OnlyResult 2 is reported (29.3); Result 1 (28.2) is believed to be lowbecause of incomplete extraction.

TABLE 4 Aripiprazole Flash-Melt Tablets; IND Stability Study - 30-mgPrototype II (%) calculated from the area under the chromatogram peaknormalized for the area under the entire chromatogram Metabolite ofaripiprazole/ oxidation N-oxide of Unknown product aripiprazolearipiprazole Impurities Potency % % % % Total Potency Potency (ReportedTime Point and Storage RRT RRT RRT RRT Impurities (Result #1) (Result#2) Result) Condition 0.91 1.00 1.08 in ( ) % mg/tab mg/tab mg/tabInitial 0.05 99.95 — 0.05 28.86 29.78 29.3  1 day @ 25 C./75% RH (open)0.07 99.88 0.05 — 0.12 29.01 NP 29.0  4 days @ 25 C./HIL/UVA (exposed)0.05 99.91 0.05 — 0.09 29.20 NP 29.2  4 days @ 25 C./HIL/UVA (wrapped)0.06 99.94 — — 0.06 29.54 NP 29.5  1 week @ 25 C./75% RH (open) 0.0899.86 0.06 — 0.14 28.94 NP 28.9  2 wks @ 25 C./HIL/UVA (exposed) 0.0599.87 0.07 — 0.13 29.23 NP 29.2  2 wks @ 25 C./HIL/UVA (wrapped) 0.0599.95 — — 0.05 29.45 NP 29.5  2 wks @ 25 C./60% RH (closed) 0.05 99.95 —— 0.05 29.02 NP 29.0  2 wks @ 25 C./75% RH (open) 0.07 99.86 0.07 — 0.1429.79 NP 29.8  4 wks @ 25 C./60% RH (closed) 0.05 99.95 — — 0.05 29.53NP 29.5  4 wks @ 40 C./75% RH (closed) 0.05 99.95 — — 0.05 29.14 NP 29.1 4 wks @ 50 C. (closed) 0.05 99.90 0.05 — 0.10 29.68 NP 29.7 13 wks @ 25C./60% RH (closed) 0.05 99.95 — — 0.05 30.145 NP 30.1 13 wks @ 40 C./75%RH (closed) 0.06 99.88 0.06 — 0.12 29.80 NP 29.8 13 wks @ 50 C. (closed)0.07 99.83 0.10 — 0.17 30.14 NP 30.1 26 wks @ 25 C./60% RH (closed) 0.0599.95 — — 0.05 29.76 NP 29.8 26 wks @ 40 C./75% RH (closed) 0.05 99.870.07 — 0.13 28.98 NP 29.0 52 wks @ −15 C. (closed) 0.05 99.95 — — 0.0529.14 NP 29.1 52 wks @ 25 C./60% RH (closed) 0.07 99.93 — — 0.07 30.17NP 30.2 RRT = relative retention time (relative to the active compound,aripiprazole) during the chromatography analysis Comments: “—” indicatesthat no peak was detected or that the peak measured less than thereporting limit (<0.05 I.I.) “NP” indicates, “Not Performed”

1. A formed pharmaceutical product comprising: (a) a pharmaceuticallyactive ingredient; and (b) a calcium metasilicate excipient having anaspect ratio of average major axial diameter/average minor axialdiameter of from about 1.3:1 to about 2.6:1, and an oil absorption offrom about 36 ml/100 g to about 51 ml/100 g.
 2. The formedpharmaceutical product of claim 1, wherein the pharmaceutical product isin tablet form.
 3. The formed pharmaceutical product of claim 1, whereinthe pharmaceutical product is in granular form.
 4. The formedpharmaceutical product according to claim 1, further comprising adisintegrant selected from the group consisting of starch, modifiedstarch, pregelatinized starch, cellulose, chemically-modified cellulose,sugars, crospovidone and croscarmellose.
 5. A formed pharmaceuticalproduct comprising: (a) a pharmaceutically active ingredient; and (b) acalcium metasilicate excipient having an aspect ratio (average majoraxial diameter/average minor axial diameter), and an oil absorptionrange defined by the aspect ratio and oil absorption range defined bythe aspect ratio and oil absorption of: (i) crystalline alpha triclinicCaSiO₃ from Aldrich Chemical Company; and (ii) crystalline meta CaSiO₃from Alfa Aesar.
 6. The formed pharmaceutical product according of claim5, wherein the crystalline alpha triclinic CaSiO₃ from Aldrich ChemicalCompany, and the crystalline meta CaSiO₃ from Alfa Aesar, each has aboutthe specifications for surface area, bulk density, true density andvolatiles set forth in Table 1 for those materials.
 7. The formedpharmaceutical product of claim 5 or claim 6, wherein the pharmaceuticalproduct is in tablet form.
 8. The formed pharmaceutical product of claim5 or claim 6, wherein the pharmaceutical product is in tablet form. 9.The formed pharmaceutical product of claim 5 or claim 6, furthercomprising a disintegrant selected from the group consisting of starch,modified starch, pregelatinized starch, cellulose, chemically-modifiedcellulose, sugars, crospovidone and croscarmellose.
 10. The formedpharmaceutical product comprising: (a) a pharmaceutically activeingredient; and (b) a calcium metasilicate excipient selected from thegroup consisting of; (i) crystalline alpha triclinic CaSiO₃ from AldrichChemical Company; and (ii) crystalline meta CaSiO₃ from Alfa Aesar. 11.The formed pharmaceutical product according of claim 10, wherein thecrystalline alpha triclinic CaSiO₃ from Aldrich Chemical Company, andthe crystalline meta CaSiO₃ from Alfa Aesar, each has about thespecifications for surface area, bulk density, true density andvolatiles set forth in Table 1 for those materials.
 12. The formedpharmaceutical product of claim 10 or 11, wherein the pharmaceuticalproduct is in tablet form.
 13. The formed pharmaceutical product ofclaim 10 or 11, wherein the pharmaceutical product is in granular form.14. The formed pharmaceutical product of claim 10 or claim 11, furthercomprising a disintegrant selected from the group consisting of starch,modified starch, pregelatinized starch, cellulose, chemically-modifiedcellulose, sugars, crospovidone and croscarmellose.
 15. A formed productcomprising: (a) a disintegrant; and (b) a dehydrated calciummetasilicate excipient having an aspect ratio (average major axialdiameter/average minor axial diameter) of from about 1.3:1 to about2.6:1, and an oil absorption of 36 ml/100 g to about 51 ml/100 g.wherein the formed product disintegrates in about 10 seconds or lesswhen immersed in water.
 16. A formed product comprising: (a) adisintegrant; and (b) a dehydrated calcium metasilicate excipient havingan aspect ratio (average major axial diameter/average minor axialdiameter), and an oil absorption range about within the aspect ratiorange and oil absorption range defined by the aspect ratio and oilabsorption of: (i) crystalline alpha triclinic CaSiO₃ from AldrichChemical Company; and (ii) crystalline meta CaSiO₃ from Alfa Aesar.wherein the formed product disintegrates in about 10 seconds or lesswhen immersed in water.
 17. The formed product of claim 16, wherein thecrystalline alpha triclinic CaSiO₃ from Aldrich Chemical Company, andthe crystalline meta CaSiO₃ from Alfa Aesar, each has about thespecifications for surface area, bulk density, true density andvolatiles set forth in Table 1 for those materials.
 18. A formed productcomprising: (a) a disintegrant; and (b) a calcium silicate excipientselected from the group consisting of: (i) crystalline alpha triclinicCaSiO₃ from Aldrich Chemical Company; (ii) crystalline meta CaSiO₃ fromAlfa Aesar; wherein the formed product disintegrates in about 10 secondsor less when immersed in water.
 19. The formed product of claim 18,wherein the crystalline alpha triclinic CaSiO₃ from Aldrich ChemicalCompany, and the crystalline meta CaSiO₃ from Alfa Aesar, each has aboutthe specifications for surface area, bulk density, true density andvolatiles set forth in Table 1 for those materials.
 20. A formedpharmaceutical product comprising: (a) a pharmaceutically activeingredient; and (b) a calcium silicate excipient selected from the groupconsisting of: (i) crystalline alpha triclinic CaSiO₃ from AldrichChemical Company; (ii) crystalline meta CaSiO₃ from Alfa Aesar; and(iii) crystalline alpha triclinic calcium silicate from TomitaPharmaceutical Co.
 21. The formed product of claim 20, wherein thecrystalline alpha triclinic CaSiO₃ from Aldrich Chemical Company, andthe crystalline meta CaSiO₃ from Alfa Aesar, each has about thespecifications for surface area, bulk density, true density andvolatiles set forth in Table 1 for those materials, and the crystallinealpha triclinic calcium silicate from Tomita Pharmaceutical Co., meetsthe following specifications: 1 to 15 m²/gm surface area; 0.50 to 0.63g/cc bulk density; 2.4 to 2.9 g/cc true density; and less than 1% w/wvolatiles.
 22. An oral dosage composition comprising a calciummetasilicate having an aspect ratio (average major axialdiameter/average minor axial diameter) of from about 1.3:1 to about2.6:1, and an oil absorption of from about 36 ml/100 g to about 51ml/100 g.
 23. The oral dosage composition according to claim 22, whereinthe calcium metasilicate is dehydrated.
 24. The oral dosage compositionaccording to claim 22, wherein the calcium metasilicate is wollastonite.25. The oral dosage composition according to claim 22, furthercomprising one or more ingredients selected from the group consisting oforganoleptic enhancing agents, abrasives, disintegration aids,therapeutic agents and thickening agents.
 26. The oral dosagecomposition according to claim 25, wherein the organoleptic enhancingagent comprises one or more ingredients selected from the groupconsisting of humectants, sweeteners, flavorants and colorants.
 27. Anoral dosage composition comprising: a calcium metasilicate having anaspect ratio (average major axial diameter/average minor axial diameter)of from about 1.3:1 to about 2.6:1, and an oil absorption of from about36 ml/100 g to about 51 ml/100 g; a disintegration aid; and anorganoleptic agent.
 28. The oral dosage composition of claim 27, furthercomprising one or more ingredients selected from the group consisting ofthickening agents, therapeutic agents, sweeteners, and abrasives. 29.The oral dosage composition of claim 27, wherein the organolepticenhancing agent comprises one or more ingredients selected from thegroup consisting of humectants, sweeteners, flavorants and colorants.30. An oral dosage composition comprising a calcium metasilicate havingan aspect ratio (average major axial diameter/average minor axialdiameter) of from about 1.3:1 to about 2.6:1, and an oil absorption offrom about 36 ml/100 g to about 51 ml/100 g.
 31. The oral tabletcomposition according to claim 30, wherein the calcium metasilicate isdehydrated.
 32. The oral tablet composition according to claim 30,wherein the calcium metasilicate is wollastonite.
 33. The oral dosagecomposition of claim 30, further comprising one or more ingredientsselected from the group consisting of organoleptic enhancing agents,abrasives, disintegration aids, therapeutic agents and thickeningagents.
 34. The oral tablet composition according to claim 33, whereinthe organoleptic enhancing agent comprises one or more ingredientsselected from the group consisting of humectants, sweeteners,flavorants, and colorants.